computation

Review
Computational Modelling and Simulation of Scaffolds for Bone
Tissue Engineering
Haja-Sherief N. Musthafa 1, * , Jason Walker 2 and Mariusz Domagala 3

1 Department of Computer Science, Electrical Engineering and Mathematical Sciences, Western Norway
University of Applied Sciences, 5063 Bergen, Norway
2 Center for Design and Manufacturing Excellence, The Ohio State University, Columbus, OH 43210, USA;
[email protected]
3 Department of Mechanical and Marine Engineering, Western Norway University of Applied Sciences,
5063 Bergen, Norway; [email protected]
* Correspondence: [email protected]

Abstract: Three-dimensional porous scaffolds are substitutes for traditional bone grafts in bone tissue
engineering (BTE) applications to restore and treat bone injuries and defects. The use of computational
modelling is gaining momentum to predict the parameters involved in tissue healing and cell
seeding procedures in perfusion bioreactors to reach the final goal of optimal bone tissue growth.
Computational modelling based on finite element method (FEM) and computational fluid dynamics
(CFD) are two standard methodologies utilised to investigate the equivalent mechanical properties of
tissue scaffolds, as well as the flow characteristics inside the scaffolds, respectively. The success of a
computational modelling simulation hinges on the selection of a relevant mathematical model with
proper initial and boundary conditions. This review paper aims to provide insights to researchers
regarding the selection of appropriate finite element (FE) models for different materials and CFD
models for different flow regimes inside perfusion bioreactors. Thus, these FEM/CFD computational
models may help to create efficient designs of scaffolds by predicting their structural properties and
their haemodynamic responses prior to in vitro and in vivo tissue engineering (TE) applications.

Keywords: computational design; computational modelling; computer simulation; finite element

Citation: N. Musthafa, H.-S.; Walker,
method; computational fluid dynamics; laminar flow; turbulent flow; perfusion bioreactor; bone
J.; Domagala, M. Computational tissue engineering; bone scaffolds
Modelling and Simulation of Scaffolds
for Bone Tissue Engineering.
Computation 2024, 12, 74.
https://doi.org/10.3390/ 1. Introduction
computation12040074 Bones are one of the most vital organs in the human body. They contain a reservoir of
Academic Editor: Simeone Marino minerals that provide protection for inner organs and support for muscles and physical
activities. Bone tissue is arranged as inner spongy cancellous bone of 75% to 95% porosity
Received: 4 March 2024 with a mean pore size of 200 µm to 600 µm diameter and outer compact cortical bone of
Revised: 26 March 2024
5% to 10% porosity with 10 µm to 100 µm pore diameter [1]. Ageing, trauma, bone loss,
Accepted: 2 April 2024
cancer, infection, and metabolic bone disorders are causes of bone defects and injuries. Bone
Published: 4 April 2024
grafts are conventionally used for bone tissue reconstruction. However, they come with
disadvantages such as infection, immune rejection on the host site, lack of vascularisation,
disease transmission and increased patient morbidity [2].
Copyright: © 2024 by the authors.
Bone tissue engineering (BTE) is an interdisciplinary bioengineering field that com-
Licensee MDPI, Basel, Switzerland. bines life sciences, engineering, materials, and physio-chemical and biological components
This article is an open access article to restore and replace injured and damaged bone tissues with new biological tissues [3–5].
distributed under the terms and BTE procedures typically utilise three-dimensional (3D) porous temporary support struc-
conditions of the Creative Commons tures known as scaffolds made of various materials to neo-tissues during regeneration
Attribution (CC BY) license (https:// (Figure 1). These scaffolds assist stem cells in surviving, proliferating, migrating, and
creativecommons.org/licenses/by/ differentiating into various functional tissues [6]. They achieve this by providing a net-
4.0/). work of interconnected pores and struts that not only support mechanical loading but

Computation 2024, 12, 74. https://doi.org/10.3390/computation12040074 https://www.mdpi.com/journal/computation

Computation 2024, 12, 74 2 of 31

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differentiating into various functional tissues [6]. They achieve this by providing a net-
work of interconnected
differentiating poresfunctional
into various and strutstissues
that not[6].only
Theysupport
achieve mechanical loading abut
this by providing also
net-
enable
work efficient mass
of interconnected transport,
pores allowing
and struts for the
that notfor movement
only of nutrients and waste mate-
also enable efficient mass transport, allowing thesupport
movementmechanical loading
of nutrients andbut also
waste
rials [7,8].
enable The degradation
efficient mass rate of
transport, scaffolds
allowing formust
the be near the
movement ofneo-tissue
nutrients growth
and waste rate in the
mate-
materials [7,8]. The degradation rate of scaffolds must be near the neo-tissue growth rate in
regeneration
rials of bone tissues (Figures 1 and 2). Ensuring that the degradation
the regeneration of bone tissues (Figures 1 and 2). Ensuring that the degradation rates the
[7,8]. The degradation rate of scaffolds must be near the neo-tissue growth raterates
in areare
synchronised
regeneration with
of new
bone tissue
tissues growth
(Figures 1is crucial
and 2). for maintaining
Ensuring that the structural
degradation
synchronised with new tissue growth is crucial for maintaining structural integrity and integrity
rates and
are
supporting
supportingthe
synchronised healing
thewith newprocess
healing process [9,10]. This
tissue growth
[9,10]. This
is synchronisation
crucial for maintaining
synchronisation minimises
structural
minimises the
the inflammation
integrity
inflammation and
risk
riskand
andmechanical
supporting failure
the healing
mechanical while[9,10].
process
failure while promoting naturaland
This synchronisation
promoting natural andefficient
efficient tissue
minimises
tissue regeneration
the inflammation
regeneration [11].
[11].
risk and mechanical failure while promoting natural and efficient tissue regeneration [11].

Figure
Figure1.1.Illustration
Illustration of
Illustration of scaffolds-based BTE. TGF-β:
scaffolds-based BTE.
scaffolds-based TGF-β:Transforming
TransformingGrowth
GrowthFactor-β,
Factor-β, BMP:
BMP: Bone
Bone
Morphogenetic
Morphogenetic Proteins,
Proteins, IGF:
IGF: Insulin-like
Insulin-like Growth
Growth Factor,
Factor, FGF:
FGF: Fibroblast
Fibroblast Growth
Growth Factor,
Factor,
Morphogenetic Proteins, IGF: Insulin-like Growth Factor, FGF: Fibroblast Growth Factor, MSCs:
MSCs:
MSCs:
Mesenchymal
Mesenchymal Stem Cells, EPC: Endothelial
Endothelial ProgenitorCell,
Cell, iPSC:Induced
Induced Pluripotent Stem Cells.
Mesenchymal Stem Stem Cells,
Cells, EPC:
EPC: Endothelial Progenitor
Progenitor Cell, iPSC:
iPSC: Induced Pluripotent
Pluripotent Stem
Stem Cells.
Cells.
Reproduced
Reproducedwith withpermission
permission from Ref.
Ref. [12]
[12]CC
CCBYBY4.0.
4.0.
Reproduced with permission from Ref. [12] CC BY 4.0.

Figure 2. (A–D) Implantation of a composite scaffold on a tibial bone defect region. (E) Bone remod-
Figure 2. (A–D) Implantation of a composite scaffold on a tibial bone defect region. (E) Bone
Figure 2. and
elling in (A–D)
outImplantation
of the scaffoldofwith
a composite scaffold
white triangles on a tibial
denoting bone defect
the external region. of
boundaries (E)the
Bone remod-
scaffold.
remodelling
elling in and in and
out of outscaffold
the of the scaffold
with withtriangles
white white triangles
denotingdenoting
the the external
external boundaries
boundaries of the of the
scaffold.
Reproduced with permission from Ref. [13] CC BY 4.0.
scaffold. Reproduced
Reproduced with permission
with permission from Ref.from
[13] Ref. [13]4.0.
CC BY CC BY 4.0.
Computation 2024, 12, 74 3 of 29

Computational modelling utilises mathematical models to study the complex pro-

cesses of a physical system using high-end computational resources. This technique in-
volves modifying inputs and boundary conditions within computer simulations to facilitate
the exploration and analysis of different scenarios and outcomes in the models [14–16]. The
advantage of simulation is that one can evaluate the designed scaffolds before fabrication,
ex vivo testing and in vivo implantation to save time and cost while obtaining valuable
information about scaffold designs [17,18]. The other advantage is that one can virtually
evaluate many scaffolds without fabrication by changing the related geometry and material
properties [19,20]. The results from the computational simulation are usually validated
through comparison with experimental studies [21,22]. Computational methods have been
used to design scaffold architectures [23,24], to predict equivalent mechanical properties of
scaffolds under diverse loading conditions using the finite element method (FEM) [25–27],
and to predict their flow properties under different flow scenarios using computational
fluid dynamics (CFD) [28,29]. They are also applied to model the degradation profiles of
scaffolds in hydrolytic degradation and erosion environments [30,31], to simulate bone
ingrowth or bone remodelling within scaffolds [32] and to simulate the vascularisation of
blood vessels [33]. The advantage of such computational modelling lies in its capacity to
predict scenarios that cannot otherwise be monitored in real-time, contributing proactive
knowledge into potential outcomes; the key to successful prediction depends on choosing
suitable models for given problems. The research questions which are addressed in this
review article for computational modelling in BTE are:
1. How do a scaffold’s architecture and morphological parameters affect its equivalent
mechanical properties and permeability?
2. How do the scaffolds behave under different loading conditions and different fluid
flow conditions while transporting materials such as nutrients and waste materi-
als? How do their equivalent mechanical properties and flow properties vary in
such scenarios?
3. What kind of material models can be applied for FEM-based structural analysis
of scaffolds, and what kind of fluid flow models can be utilised for CFD-based
permeability analysis of scaffolds?

2. Computational Modelling of Mechanical Behaviour and Permeability of Scaffolds

2.1. Design of Scaffolds
2.1.1. Essentials of Scaffolds
Scaffolds for BTE are temporary porous biomaterial structures that act as supporting
frameworks for incoming cells to adhere to, multiply and finally differentiate into different
functional bone tissues. They must be: (i) nontoxic to host tissues (i.e., biocompatible),
(ii) able to degrade their structure to give space for the growing bone cells (i.e., biodegrad-
able) [34], (iii) able to permit the cells to stick and multiply on their surfaces to generate
extracellular matrix (i.e., osteoconductive) [35], (iv) able to induce neo-bone tissues through
mechanical stimulus (i.e., osteoinductive) [36], (v) able to form bone materials with the
help of bone-forming cells ‘osteoblasts’ (i.e., osteogenic), (vi) able to integrate existing
osseous tissues with their load-bearing surfaces (osteointegration) [37], (vii) exhibit ap-
propriate morphological characteristics like pore size, porosity, and pore connectivity [38],
and (viii) mirror the mechanical properties of the host tissues, including Young’s modulus
and compressive strength. These properties of scaffolds are influenced by their materi-
als, such as synthetic and natural polymers, bio-composites, metal alloys and ceramics
(Figures 3 and 4) [39–41].
Computation 2024, 12, 74 4 of 31
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Figure 3. The characteristics of a BTE scaffold and its related supportive functions [42].
Figure 3. The characteristics of a BTE scaffold and its related supportive functions [42].
Computation 2024, 12, 74 5 of 31
Computation 2024, 12, 74 5 of 29

Figure
Figure 4.
4. Factors requiredfor
Factors required fordesigning
designing scaffolds.
scaffolds. Reproduced
Reproduced withwith permission
permission from[43]
from Ref. Ref.
CC[43]
BYCC
4.0.
BY 4.0.
2.1.2. Types of Designs
2.1.2. There
Typesare of Designs
two types of scaffold designs based on the architecture: non-parametric and
parametric
There are two 5)
(Figure [44].of
types Non-parametric
scaffold designs designs
basedareonbased on traditional
the architecture: lattice geome-
non-parametric
tries such as simple cubic, body-centred cubic (BCC), face-centred
and parametric (Figure 5) [44]. Non-parametric designs are based on traditional cubic (FCC) [45,46],lattice
octet,
truncated octahedron [47], diamond, truncated cube [48], fluorite, kelvin
geometries such as simple cubic, body-centred cubic (BCC), face-centred cubic (FCC) cell [49], iso truss,
re-entrant,
[45,46], Weaire–Phelan
octet, and honeycomb
truncated octahedron [50]. An
[47], diamond, advantage
truncated of[48],
cube non-parametric
fluorite, kelvindesign
cell
is that the scaffolds are more accessible to manufacture due to their simple
[49], iso truss, re-entrant, Weaire–Phelan and honeycomb [50]. An advantage of non-par- geometries, as
they dodesign
ametric not require
is thatspecialised
the scaffolds algorithms
are more to generate.
accessible to Parametric
manufacture designs, on the
due to their other
simple
hand, leverage more complex algorithms to create complicated structures,
geometries, as they do not require specialised algorithms to generate. Parametric designs, such as Triply
Periodic
on Minimal
the other hand,Surfaces
leverage(TPMS) [51] andalgorithms
more complex Voronoi structures
to create[52,53]. Modern
complicated additive
structures,
manufacturing technologies (AM) are capable of producing such complex
such as Triply Periodic Minimal Surfaces (TPMS) [51] and Voronoi structures [52,53]. designs [54,55].
Modern additive manufacturing technologies (AM) are capable of producing such com-a
Scaffolds based on TPMS can be generated through trigonometric equations and provide
smooth surface devoid of sharp edges, zero mean curvature, a high surface-to-area ratio,
plex designs [54,55]. Scaffolds based on TPMS can be generated through trigonometric
well-interconnected non-tortuous pores, and superior material permeability compared to
equations and provide a smooth surface devoid of sharp edges, zero mean curvature, a
scaffolds based on non-parametric designs [56,57]. Voronoi scaffolds are designed based
high surface-to-area ratio, well-interconnected non-tortuous pores, and superior material
on Voronoi tessellation using randomly distributed seeding points to create polyhedral
permeability compared to scaffolds based on non-parametric designs [56,57]. Voronoi
cells scaled to form pores and struts of structures similar to trabecular bones [58,59]. Apart
scaffolds are designed based on Voronoi tessellation using randomly distributed seeding
from TPMS and Voronoi structures, distinct research works are being performed to design
points to create polyhedral cells scaled to form pores and struts of structures similar to
unique stochastical structures to mimic the bone structures using level set equations with
trabecular bones [58,59]. Apart from TPMS and Voronoi structures, distinct research
weight functions [60], an anisotropic spinodal phase decomposition with Gaussian random
works are being performed to design unique stochastical structures to mimic the bone
fields (GRF) [61–63], and an iterative topological network optimisation based on a graph of
structures using level set equations with weight functions [60], an anisotropic spinodal
trabecular bone [64,65].
phase decomposition with Gaussian random fields (GRF) [61–63], and an iterative topo-
Further, the scaffolds can be classified into uniform and functionally graded scaf-
logical network
folds (FGS). optimisation
Uniform scaffoldsbased
have on
theasame
graphporosity
of trabecular bone [64,65].
throughout their structure, whereas
Further, the scaffolds can be classified into uniform and functionally
FGS have gradient porosities based on relative density or cell size variation graded scaffolds
[66,67]. The
(FGS).
gradient in an FGS may be designed to imitate the characteristics of native tissues. FGS
Uniform scaffolds have the same porosity throughout their structure, whereas Usu-
have
ally, gradient porosities
scaffold design based
begins on relative
with obtainingdensity or cell size
anatomical variation
shapes [66,67]. The
from imaging gradi-
tools like
ent in an FGS may be designed to imitate the characteristics of native
computer tomography (CT) [68,69] and magnetic resonance imaging (MRI), or modelling tissues. Usually,
scaffold
cellular design
lattices begins with obtaining anatomical
using computer-aided design (CAD) shapes from imaging
software tools like
or specialised com-
programs
puter tomography (CT) [68,69]
(Supplementary Materials Table S1). and magnetic resonance imaging (MRI), or modelling
Computation 2024, 12, 74 6 of 31

Computation 2024, 12, 74 cellular lattices using computer-aided design (CAD) software or specialised 6programs
of 29
(Supplementary Materials Table S1).

Figure 5. 5.
Figure Types
Typesofofscaffold
scaffold designs basedon
designs based ontheir
their architectures.
architectures. Their
Their related
related structures
structures can becan be
viewed in Supplementary Materials Figures S1–S3.
viewed in Supplementary Materials Figures S1–S3.

2.1.3. Influence of Morphological Parameters on Mechanical Behaviour and Permeability

2.1.3. Influence of Morphological Parameters on Mechanical Behaviour and Permeability
The morphological parameters of scaffolds, such as pore size, porosity, pore intercon-
The morphological parameters of scaffolds, such as pore size, porosity, pore inter-
nections and pore shape, all influence osteogenesis. A large pore size, for example, leads to
connections and and
higher porosity pore shape,
a larger all influence
surface osteogenesis.
area for the A largeand
cells to live, multiply pore size, for example,
differentiate into
leads to higher porosity and a larger surface area for the cells to live, multiply
specialised bone tissues. The morphology of scaffolds and their effective pore interconnec- and differ-
entiate
tions into
playspecialised
a crucial rolebone tissues. The
in facilitating morphology
oxygen exchange and of scaffolds and theirwithin
nutrient delivery effective
the pore
interconnections play a crucial role in facilitating oxygen exchange and nutrient delivery
scaffolds for cell growth, which is essential for successful tissue regeneration [70]. However,
increased
within porosity compromises
the scaffolds for cell growth,mechanical
which is strength,
essentialimpacting the scaffold’s
for successful tissueability to
regeneration
withstand
[70]. However, applied loads [71].
increased porosity compromises mechanical strength, impacting the scaf-
fold’s
2.2. ability to withstand
Simulation applied
of Mechanical loads
Behaviour [71].
of BTE Scaffolds
FEM for Prediction of Mechanical Properties
2.2. Simulation of Mechanical Behaviour of BTE Scaffolds
The mechanical properties of the scaffolds, such as effective elastic modulus com-
FEM for Prediction
pressive and tensileofstrengths,
Mechanical Properties
depend on their material properties and architectures [72].
Scaffolds are subjected
The mechanical to variousof
properties types
the of loading, including
scaffolds, shear, bending,
such as effective elastictorsion,
modulusten- com-
sion, and compression, after they are implanted inside the body [73,74]. In load bearing
pressive and tensile strengths, depend on their material properties and architectures [72].
BTE applications, scaffolds must support loads ranging from hundreds to thousands of
Scaffolds are subjected to various types of loading, including shear, bending, torsion, ten-
newtons, making their mechanical properties crucial [75,76]. It is indispensable for the
sion, and compression,
scaffolds to withstand after they loads
significant are implanted inside thetobody
without collapsing achieve[73,74]. In load
the goal bearing
of bone
BTE applications,
tissue generation.scaffolds
FEM is amust support
numerical toolloads
used ranging from hundreds
to solve partial differentialtoequations
thousands of
newtons, making their mechanical properties crucial [75,76]. It is indispensable
(PDEs) in real-time engineering problems, enabling the prediction of mechanical properties. for the
scaffolds to withstand
This capability significant
is valuable loads without
for optimising collapsing
the scaffolds to achieve
by modifying theirthe goal of bone tis-
morphological
sue generation. FEM is a numerical tool used to solve partial differential equations (PDEs)
in real-time engineering problems, enabling the prediction of mechanical properties. This
 Computation 2024, 12, 74 7 of 31

Computation 2024, 12, 74 7 of 29

capability is valuable for optimising the scaffolds by modifying their morphological pa-
rameters [77,78].
parameters In In
[77,78]. FEM,FEM,thethe
scaffold geometry
scaffold geometryis partitioned into into
is partitioned a finite number
a finite of ele-of
number
ments using the process of meshing. Generally, increasing the number of
elements using the process of meshing. Generally, increasing the number of finite elements finite elements
improves the
improves the accuracy
accuracy andand fidelity
fidelity of
of simulation
simulation results
results but
but also
alsoleads
leadstotoananincrease
increaseinin
computationtime
computation time[79].
[79]. An
An FEFE model
model combines
combines FE FE meshes
meshesand andmaterial
materialproperties
propertiessuch suchasas
Poisson’sratio
Poisson’s ratioand
and Young’s
Young’s modulus.
modulus. TheThe choice
choice of ofmodel
modeldepends
dependson onscaffold
scaffoldmaterials,
materials,
whichvary
which varyfrom
from elastic,
elastic, plastic,
plastic, hyperelastic,
hyperelastic, poor
poor elastic,
elastic, and
andelastoplastic
elastoplasticto toviscoelastic
viscoelastic
models, which can express one or more linear, bilinear, multilinear,
models, which can express one or more linear, bilinear, multilinear, and non-linear and non-linear behav-be-
iours (Figure 6) (Table 1). By applying boundary conditions such as force,
haviours (Figure 6) (Table 1). By applying boundary conditions such as force, acceleration acceleration
loads,pressure
loads, pressure and
and displacement
displacement restraints
restraints toto FE
FE models,
models,various
variousmechanical
mechanicalproperties,
properties,
including displacement, principal strain, component strain, principalstress,
including displacement, principal strain, component strain, principal stress,vonvonMises
Mises
stressand
stress andcomponent
componentstressstressareare computed
computed forfor different
different materials
materials [80,81].
[80,81]. TheseThese calcula-
calculations
tions
are are conducted
conducted throughthrough static, quasi-static,
static, quasi-static, and buckling
and buckling analyses.analyses. The workflow
The workflow (Figure 7)
(Figure
of 7) of an imaging-based
an imaging-based FEM computational
FEM computational modellingmodelling
process ofprocess of TE scaffolds
TE scaffolds is given isby
given by Imran
Imran et al. [82]. et al. [82].

Figure 6. Different stages of compressive behaviour of lattice structures. Reproduced with permis-
Figure 6. Different stages of compressive behaviour of lattice structures. Reproduced with permission
sion from Ref. [83] CC BY-NC-ND 4.0.
from Ref. [83] CC BY-NC-ND 4.0.
One of the basic FEM-based material models for structural analysis is a linear model
One of the basic FEM-based material models for structural analysis is a linear model
which obeys Hooke’s Law. This linear model substantiates a linear association between
which obeys Hooke’s Law. This linear model substantiates a linear association between
the applied force and the resulting displacement. In a linear isotropic material model, the
the applied force and the resulting displacement. In a linear isotropic material model,
properties of materials do not change with direction. Musthafa et al. [84] designed gyroid-
the properties of materials do not change with direction. Musthafa et al. [84] designed
based TPMS scaffolds of titanium alloys with different pore sizes using the signed dis-
gyroid-based TPMS scaffolds of titanium alloys with different pore sizes using the signed
tance field method and applied compressive loading using linear elastic FEM-based sim-
distance field method and applied compressive loading using linear elastic FEM-based
ulation to evaluate their effective elastic modulus for BTE applications. In this research,
simulation to evaluate their effective elastic modulus for BTE applications. In this research,
methods to create surface/volume/FE meshes from a gyroid lattice were explained to cre-
methods to create surface/volume/FE meshes from a gyroid lattice were explained to
ate FE models for the compressive loading simulation (Figure 8). The results revealed that
create FE models for the compressive loading simulation (Figure 8). The results revealed
the predicted elastic moduli of the scaffolds were in the range of 0.05 to 1.93 GPa and gave
that the predicted elastic moduli of the scaffolds were in the range of 0.05 to 1.93 GPa and
an insight into how the required mechanical properties can be achieved by tuning the
gave an insight into how the required mechanical properties can be achieved by tuning
morphological parameters of the scaffold [84]. However, it is imperative to note that this
the morphological parameters of the scaffold [84]. However, it is imperative to note that
linearity holds only within the linear elastic region of a material. Linear elastic models are
this linearity holds only within the linear elastic region of a material. Linear elastic models
suitable only for small deformations, while summations involving large deformations
are suitable only for small deformations, while summations involving large deformations
necessitate the use of non-linear elastic models to predict yielding behaviour accurately [85].
Computation 2024, 12, 74 8 of 31
Computation 2024, 12, 74 8 of 29

necessitate the use of non-linear elastic models to predict yielding behaviour accurately
A[85]. A similar
similar linear isotropic
linear isotropic elasticwas
elastic trend trend wasinfound
found in Ti6Al4V
Ti6Al4V scaffolds scaffolds based
based dental dental
implants
implants
for for periodontal
periodontal diseases
diseases (Figure 9).(Figure 9).

Figure 7.7. An
Figure An image-based
image-based FEM
FEM computational
computational workflow
workflow for
for BTE
BTE scaffolds
scaffolds using
using FEM
FEM and
andCFD
CFD
modelling [82].
modelling [82].
Computation 2024, 12, 74 9 of 29
Computation 2024, 12, 74 9

Figure 8. (a) An FE volume mesh for an FE model from an implicit body of a cuboid gyroid sca
Figure 8. (a) An FE volume mesh for an FE model from an implicit body of a cuboid gyroid scaffold
(conversion of the given implicit body to a surface mesh, to a volume mesh with tetrahedral
(conversion of the given implicit body to a surface mesh, to a volume mesh with tetrahedral elements
ments and a FE volume mesh with quadratic order), (b) structural analysis of an FE model u
and a FE volumecompressive
mesh with quadratic order),
loading. (c) (b) structural
von Mises contouranalysis
of PS550of(Pore
an FEsize
model under
500 µm andcompressive
Strut size 300 µm) gy
loading. (c) von scaffold,
Mises contour
and (d)ofdisplacement
PS550 (Pore size 500 µm
contour and Strut
of PS550. size 300 µm)
Reproduced gyroid
with scaffold,
permission andRef. [84] CC
from
(d) displacement4.0.
contour of PS550. Reproduced with permission from Ref. [84] CC BY 4.0.
Computation 2024,
Computation 12,12,
2024, 74 74 10 of1031of 29

Figure 9. Prediction of von Mises stress (S) and max principal strain (E) of scaffolds attached to
Figure 9. Prediction of von Mises stress (S) and max principal strain (E) of scaffolds attached to dental
dental implants using FEM-based linear isotropic models. Reproduced with permission from Ref.
implants using FEM-based
[86] CC BY-NC-ND 4.0. linear isotropic models. Reproduced with permission from Ref. [86] CC
BY-NC-ND 4.0.
In bilinear isotropic (BISO) hardening models, the stress and strain vary even after
In bilinear isotropic (BISO) hardening models, the stress and strain vary even after at-
attaining maximum plastic deformation. A bilinear isotropic hardening model was ap-
taining maximum
plied with plastic
quasi-static deformation.
compressive A bilinear simulation
loading-based isotropic hardening
using FEMmodel by Zhangwas et applied
al.
with quasi-static compressive loading-based simulation using
[87] to predict local strain distributions, effective Young’s modulus, and compressive FEM by Zhang et al. [87] to
predict
strengthlocal
of strain distributions, effective Young’s modulus,
poly (ε-caprolactone)/nanohydroxyapatite and compressive
scaffolds strengthbone
for osteochondral of poly
(ε-caprolactone)/nanohydroxyapatite
defects. The objective of this work was to evaluate the effects of pore shape on scaffolds’ of
scaffolds for osteochondral bone defects. The objective
this work wasproperties.
mechanical to evaluateAthe effects
mesh sizeof of
pore shape
0.125 mmonwas scaffolds’
utilisedmechanical
for linear properties.
tetrahedralAele- mesh
size of 0.125 mm was utilised for linear tetrahedral elements
ments to create FE meshes of scaffolds, ensuring convergence in FE modelling. The FEto create FE meshes of scaffolds,
ensuring
outcomes convergence
displayed ainlinear
FE modelling.
correlation The FE outcomes
between displayed
the porosities anda linear
Young’s correlation
moduli of between
the
the porosities
scaffolds, and Young’s
similar to that ofmoduli of the scaffolds,
osteochondral bone [87].similar to that of osteochondral bone [87].
InInelastoplastic materialsmodels,
elastoplastic materials models, thethe non-linear
non-linear performance
performance of theofmaterials
the materials
is de- is
described
scribed asas bilinear
bilinear [88][88] or multilinear
or multilinear [89] following
[89] following the of
the onset onset of plastic
plastic deformation,
deformation, dur-
during
ing whichwhich theythey
endureendure permanent
permanent deformation
deformation after theafter theare
loads loads are applied.
applied. A linear
A linear elastic
elastic
FEM mustFEM be must be initially
initially performed performed to determine
to determine whetherwhether the predicted
the predicted stress is stress
largeristhanlarger
than the yield
the yield strength
strength of theofmaterial.
the material.
Then,Then, a non-linear
a non-linear staticcan
static FEM FEM can be performed
be performed to pre- to
dict itsits
predict behaviour
behaviour in in
thethe
plastic regime
plastic regime [90]. A series
[90]. A series of of
static analyses
static analyses areare
conducted
conducted to to
analysetime-dependent
analyse time-dependentnon-linearnon-linearbehaviours
behavioursofofmaterials
materialslike likeplasticity
plasticityand andviscoelasticity.
viscoelas-
Inticity.
each In each successive
successive time step time step within
within the boundary
the series, series, boundary conditions
conditions are adjusted
are adjusted without
without consideration of inertial forces, frequency,
consideration of inertial forces, frequency, or damping effects [91]. or damping effects [91].
Rezapourianetetal.al.[92]
Rezapourian [92]designed
designedTPMS-based
TPMS-based Split-P
Split-P scaffolds
scaffolds ofof porosities
porosities in in a range
a range from
from 75% to 90% and applied a multilinear isotropic elastoplastic
75% to 90% and applied a multilinear isotropic elastoplastic model to predict the behaviour model to predict the
ofbehaviour of Ti6Al4V
Ti6Al4V scaffolds underscaffolds under loading.
compressive compressiveLinear loading. Linear
tetrahedral tetrahedral
meshes (with an meshes
element
(with
size an element
of 0.2 mm) of the sizescaffolds
of 0.2 mm) of the
were scaffolds
placed wereaplaced
between between
fixed bottom a fixed
plate andbottom
a movableplatetop
and subject
plate, a movable to a top plate,ofsubject
velocity 2 ms−1to , toa simulate
velocity ofthe2compressive
ms−1, to simulate the compressive
behaviour be-
at different strains.
haviour at different strains. The assessment of the simulation results
The assessment of the simulation results disclosed that the Split-P scaffolds exhibited adequate disclosed that the
Split-P
stress scaffolds
transfer exhibited
necessary adequateload-supporting
for enhanced stress transfer necessary
capabilityfor in enhanced
trabecular load-support-
and cortical bone
ing capability in trabecular and cortical bone applications,
applications, displaying fracture characteristics capable of sustaining normal displaying fracturebiomechanical
character-
istics capable of sustaining normal biomechanical loads [92].
loads [92].
Verma et al. [93] utilised a non-linear isotropic hardening elastoplastic model for FE
Verma et al. [93] utilised a non-linear isotropic hardening elastoplastic model for FE
simulations involving diverse compressive loading scenarios. These simulations focused
simulations involving diverse compressive loading scenarios. These simulations focused on
on a Ti6Al4V primitive (P) TPMS scaffold with 80% porosity fixed within a segmental
a Ti6Al4V primitive (P) TPMS scaffold with 80% porosity fixed within a segmental bone
defect region of a femur. The authors compared its performance against scaffolds placed within
femoral defects (Figure 10). The simulation results indicated that the porous P scaffolds provided
Computation 2024, 12, 74 11 of 31

Computation 2024, 12, 74 11 of 29

bone defect region of a femur. The authors compared its performance against scaffolds
placed within femoral defects (Figure 10). The simulation results indicated that the porous
beneficial
P scaffolds mechanical
provided stimuli to the
beneficial neighbouring
mechanical bone
stimuli totissues and transferred
the neighbouring bonemore stress
tissues to
and
these tissues due to the matching effective elastic modulus [93].
transferred more stress to these tissues due to the matching effective elastic modulus [93].

Figure 10. FEA

Figure 10. FEA ofofsolid
solidand
andporous
porousTPMS
TPMSscaffolds
scaffoldsbased
basedonon
segmental
segmental femur defect
femur forfor
defect BTE andand
BTE its
its related
related stress
stress contours
contours (units
(units areare given
given inin MPa):
MPa): (a,b)
(a,b) ImplantationofofP-TPMS
Implantation P-TPMSand
andsolid
solid scaffolds,
scaffolds,
 Computation 2024, 12, 74 12 of 31
Computation 2024, 12, 74 12 of 29

(c,d) stress distribution contours on the bone, (e,f) von Mises stress contours of P and solid scaffolds,
(c,d)
(g,h)stress
stressdistribution
distributioncontours
contourson
forthe bone,
P and (e,f)scaffolds
solid von Mises stress
at 50 MPa.contours of P and
Reproduced solid
with scaffolds,
permission
from Ref. [93] CC BY 4.0.
(g,h) stress distribution contours for P and solid scaffolds at 50 MPa. Reproduced with permission
from Ref. [93] CC BY 4.0.
A BISO model with Maxwell’s criterion was used by Vance et al. [94] to predict the
A BISO model
elastoplastic with Maxwell’s
mechanical behaviour criterion
of customisedwas used by Vance
Ti6Al4V (Ti64)et al. [94] to
sheathed predictim-
scaffold the
elastoplastic mechanical behaviour of customised Ti6Al4V (Ti64) sheathed
plants obtained from X-ray CT for segmental bone defect repair. The simulation results scaffold implants
obtained
predicted from
the X-ray
Young’sCTmodulus
for segmental
of thebone defect
implant repair.GPa,
at 11.94 Thecomparable
simulation with
results predicted
that of ex-
the Young’s modulus of the implant at 11.94 GPa, comparable with that
perimental testing (14.58 GPa). Given that its stiffness is lower than Young’s modulus of of experimental
testing (14.58
the tibia boneGPa).
(18.01Given
GPa),that
this its stiffness
suggests is the
that lower
bonethan Young’s
implant is a modulus of the tibiawith
potential candidate bone
(18.01 GPa), this suggests that the bone implant is a potential candidate with
the requisite lower stiffness required for osseointegration and bone regeneration (Figure the requisite
lower stiffness required for osseointegration and bone regeneration (Figure 11) [94].
11) [94].

Figure 11. FEM-based BISO elastoplastic model prediction of scaffolds for tibial bone defect repair.
Figure 11. FEM-based
Reproduced BISO elastoplastic
with permission model
from Ref. [94] prediction 4.0.
CC BY-NC-ND of scaffolds for tibial bone defect repair.
Reproduced with permission from Ref. [94] CC BY-NC-ND 4.0.
Huang et al. [95] comprehensively reviewed several biomaterial scaffolds for appli-
Huang et al. [95] comprehensively reviewed several biomaterial scaffolds for ap-
cations of maxillofacial BTE. They explained the technical considerations of physical prop-
plications of maxillofacial BTE. They explained the technical considerations of physical
erties (shape, porous structure, microarchitecture and mechanical), biological properties
properties (shape, porous structure, microarchitecture and mechanical), biological proper-
and biomaterials (metals, polymers, ceramics, and composites) required for essential cell
ties and biomaterials (metals,
proliferation, angiogenesis, polymers,
and ceramics,
osteogenesis and composites)
[95]. Polymeric required
materials for essential
give more control
cell proliferation, angiogenesis, and osteogenesis [95]. Polymeric materials give
over morphological parameters, biocompatibility, and biodegradation [96]. In quasi-static more
control over morphological parameters, biocompatibility, and biodegradation
compressive loading, polymer-based scaffolds undergo viscoelastic deformation after [96]. In quasi-
static compressive
yielding. loading, polymer-based
This viscoelastic behaviour can bescaffolds undergo
simulated usingviscoelastic deformation
the Prony series after
relaxation
yielding. This viscoelastic behaviour can be simulated using the Prony series
model, in which the shear and bulk moduli are described via the Prony series with the relaxation
model,
help ofin which theand
volumetric shear and bulk
deviatoric moduliofare
viscosities described
materials via the
[97,98]. TheProny series with
polymer-based the
scaf-
help of volumetric and deviatoric viscosities of materials [97,98]. The polymer-based
folds with increasing porosity lack sufficient mechanical strength for loadbearing bone scaf-
folds with increasing
applications [99]. porosity lack sufficient mechanical strength for loadbearing bone
applications [99].

Table 1. Computational modelling of mechanical behaviour using FEM.

Model Predicted Mechanical Properties Material * Remarks

Relationship between compressive modulus and
Linear isotropic Young’s modulus porosities of uniform and gradient diamond
PCL
elastic model (2D and 3D compressive responses) pored scaffolds for tissue-engineered meniscus
applications [100]
Twinning- Evaluation of morphological properties on
BISO model Effective plastic strain induced quasi-static behaviour of hallow walled lattice
plasticity steel structures under compressive loading [101]
Computation 2024, 12, 74 13 of 29

Table 1. Cont.

Model Predicted Mechanical Properties Material * Remarks

Prediction of compressive stiffness of
Linear isotropic Equivalent Young’s modulus,
PCL-ACP non-parametric scaffolds under linear
Reuss model compression Stiffness
compressive loading for BTE applications [102]
Prediction of elastoplastic nature of Split-P
Multilinear isotropic, von Mises stress, equivalent plastic
Ti6Al4V TPMS scaffolds for cortical and trabecular bone
elastoplastic model strain distributions
applications [92]
Evaluating the influence of gradient properties
Non-linear of TPMS and circular loading scaffolds on their
Plastic deformation 316L SS
elastoplastic model elastoplastic properties under static compressive
loading [103]
Evaluation of effects of unit cells of gyroid and
Raghava–Hill
Compressive stiffness and strength Ti-42Nb alloy I-WP-based bone scaffolds on their mechanical
Plasticity Model
properties under quasi-static compression [104]
Bilinear plasticity
model with isotropic
SS316 Stainless Prediction of plastic behaviour of Voronoi-based
hardening Plastic deformation
Steel honeycomb scaffolds [105]
(Li–Guo–Shim
Model)
Prediction of non-linear mechanical properties of
One term Ogden Effective compressive modulus,
AG hydrogels mesostructure-based hydrogel scaffolds using
hyper elastic model shear modulus
inverse FE simulations for TE applications [106]
5-term
Evaluation of the hyper-viscoelastic response of
Mooney–Rivlin and
Stress relaxation AG hydrogels hydrogels in compression and tension loading
2-term Ogden
for human articular cartilage [107]
models
5-term
Mooney–Rivlin
Prediction of elastic and viscoelastic behaviours
model, Prony series Tensile strength and storage
PLA of dog bone-shaped structures under tensile
relaxation model and modulus
loading [108]
Generalised Maxwell
Model (GMM)
Burgers and
Linear viscoelastic behaviour (creep Prediction of viscoelastic deformation at
Maxwell viscoelastic Polypropylene
and recovery) different pressure levels [109]
models
Development of a non-linear multiaxial
Riemann–Liouville-
Viscoelastic (creep recovery and viscoelastic model to evaluate time-dependent
based fractional POM
cyclic response) deformations responses of isotropic materials under small
viscoelastic model
deformation gradients [110]
Prediction of time-dependent viscoelastic
Maxwell, Kelvin,
Storage and loss moduli PLA behaviour of orthotropic viscoelastic materials
and Burger models
[111]
Prediction of mechanical properties of
Effective elastic moduli (Young’s Acrylic-based
Mori–Tanaka model mix-materials composites based foams with
modulus) and Poisson’s ratio photopolymers
different porosities [112]
Prediction of damage behaviour of polymer
Crushable foam Elastic modulus under quasi-static
VeroClear bone scaffolds with cubic and hexagonal
plasticity model compression
architecture [113]
Computation 2024, 12, 74 14 of 29

Table 1. Cont.

Model Predicted Mechanical Properties Material * Remarks

Performance evaluation of failure and
Johnson–Cook (JC) mechanical strength mechanisms of
damage deformation Compressive stress distribution Ti6Al4V-PCL interpenetrating phase composites (IPCs) under
model compressive loading for orthopaedic
implants [114]
Prediction of viscoelastic behaviour of polymeric
Arruda–Boyce (AB) Compressive uniaxial modulus and
PA-12 gyroid scaffolds of sheet network architecture
Model strength
with non-identical relative densities [115]
* PCL-ACP: Polycaprolactone and amorphous calcium phosphate, PCL: Polycaprolactone, PLA: Polylactic Acid,
LSCF: Lanthanum strontium cobalt ferrite, PHBV: Poly(3-hydroxybutyrate-co-3-hydroxy valerate), ABS: Acryloni-
trile Butadiene Styrene, ITO: Indium Tin Oxide, Ti6Al4V: Titanium–Aluminium–Vanadium alloy, PEEK: Polyether
ether ketone, Ti-4Nb: Titanium–Niobium alloy, N/A: Not Applicable; PA: Polyamide; AG: Alginate–Gelatin;
POM: Polyoxymethylene; SS: Stainless Steel.

2.3. Simulation of Permeability of BTE Scaffolds

Need for Permeability Simulation
Scaffolds permit the transport of nutrients from nearby tissues and provide a pathway
to eliminate waste products from the cells. Permeability refers to the ability of materials to
flow through the scaffolds and is primarily dependent on the architecture of the scaffolds.
When scaffolds possess high permeabilities and well-interconnected pore networks, a more
significant number of cells and nutrients can infiltrate the scaffolds, leading to enhanced
tissue growth [116,117]. Shear flow refers to the movement of a fluid induced by forces
within it. Wall shear stress (WSS) is a specific type of shear stress that occurs due to
varying fluid velocities along the inner surfaces of scaffold walls. WSS provides mechanical
stimuli that encourage cells to grow and differentiate into functional tissues [118,119].
Therefore, altering design parameters like pore size, architecture, and pore interconnectivity
in scaffolds can result in a different average WSS, which is instrumental in guiding cell
differentiation within these structures [120,121].
CFD is a numerical approach applied to simulate the nature of fluid flow inside
scaffolds and their related fluidic environments. CFD simulation solves the governing
mathematical equations that characterise the physical nature of fluids (e.g., pressure and
velocity) using an in silico depiction of fluidic nature in different flow situations. This
technique can be used to optimise the design of scaffolds and improve their permeability
for successful bone tissue regeneration [122,123]. For CFD simulations, two types of fluids
are considered: Newtonian and non-Newtonian fluids [124,125]. Newtonian fluids such as
water, alcohol, and glycerol have constant viscosity at constant temperatures and obey the
Newtonian law of viscosity. This law states that their shear stress is directly proportional to
the rate of change in fluid velocity. Non-Newtonian fluids such as blood and cell culture
media, which do not obey Newton’s law of viscosity, have variable viscosities dependent
on shear rate (Tables 2 and 3).

Table 2. Flow parameters in BTE from the literature.

Parameters Authors Reference

Blood flow rate in tibia = 60 mL/100 g/min Iversen et al. [126]
Blood density in bone = 1810 kg/m3 Pal et al. [127]
Blood velocity in bone marrow = 0.5 to 0.8 mm/s Bixel et al. [128]

Newtonian fluids, with their constant viscosity at a constant temperature, flow more
readily through permeable networks, while non-Newtonian fluids, owing to their variable
viscosity, exhibit higher levels of WSS. CFD simulations based on non-Newtonian fluids
give more realistic fluid flow behaviour predictions, especially in biomedical applications,
due to their more realistic representation of the variable viscosity characteristics of biological
 viscosity, exhibit higher levels of WSS. CFD simulations based on non-Newtonian fluids
give more realistic fluid flow behaviour predictions, especially in biomedical applications,
due to their more realistic representation of the variable viscosity characteristics of biolog-
ical fluids [129]. Values of WSS greater than 30 mPa have been shown to be beneficial for
Computation 2024, 12, 74 the growth of cells [130].
15 of 29
Suffo et al. discussed the differences between various turbulent flow modelling meth-
ods (Figure 12) [131]. These methods include Reynolds averaged Navier–Stokes (RANS)
such as k-ε, k-ω (Wilcox model) and k-ω SST (shear stress transport), Reynolds stress mod-
fluids [129]. Values of WSS greater than 30 mPa have been shown to be beneficial for the
els (RSM),
growth large[130].
of cells eddy simulation (LES), direct numerical simulation (DNS), the scale adap-
tive Suffo
simulation (SAS), and detached
et al. discussed eddy simulation
the differences (DES) models.
between various Theflow
turbulent authors applied
modelling
these models to different turbulent flows and utilised the knowledge
methods (Figure 12) [131]. These methods include Reynolds averaged Navier–Stokes of CFD simulation
with Fluid–Structural
(RANS) such as k-ε, k-ω Interaction (FSI) techniques
(Wilcox model) and k-ω SST [132,133].
(shearThis integration
stress transport),was specifi-
Reynolds
cally employed for turbulence flow modelling of PLA scaffolds, facilitating
stress models (RSM), large eddy simulation (LES), direct numerical simulation (DNS), the the study of
theiradaptive
scale flow properties.
simulation (SAS), and detached eddy simulation (DES) models. The authors
Pires
applied these et al. [134] provided
models a review
to different of the
turbulent challenges
flows encountered
and utilised in designing
the knowledge CFD
of CFD
applications for BTE. Notably, they explained how scaffold design parameters
simulation with Fluid–Structural Interaction (FSI) techniques [132,133]. This integration affect both
mechanical and permeability properties, as well as how CFD and FEM simulation
was specifically employed for turbulence flow modelling of PLA scaffolds, facilitating the studies
optimise
study scaffold
of their flowdesigns to achieve the goal of bone tissue regeneration [134].
properties.

Figure12.
Figure 12.Principal
Principalturbulent
turbulentCFD
CFDmethods
methods(from
(fromtop
toptotobottom:
bottom:lowest
lowestto
tohighest
highestcomputational
computational
cost) [131].
cost) [131].

Pires et al. [134] provided a review of the challenges encountered in designing CFD
applications for BTE. Notably, they explained how scaffold design parameters affect both
mechanical and permeability properties, as well as how CFD and FEM simulation studies
optimise scaffold designs to achieve the goal of bone tissue regeneration [134].
In BTE, bioreactors are employed to grow functional tissues from MSCs in controlled
in vitro conditions. This process provides a continuous supply of nutrients and the removal
of waste products prior to in vivo implantation at bone defect sites [135,136]. Implementing
a mathematical model of the process in a CFD simulation involves four key steps: designing
the geometries of scaffolds and complimentary bioreactors, selecting the appropriate flow
Computation 2024, 12, 74 16 of 29

equations, and determining the boundary and initial conditions (Figure 13) [137,138]. Thus,
the fundamentals of CFD simulations can be described in three modules:
(i) Preprocessing: This initial phase involves designing the scaffold geometry and setting
up the bioreactor geometry. Then, the fluid domain or volume is extracted using
Boolean differentiation of scaffold geometry with the bioreactor geometry (Figure 14).
The flow of either Newtonian or non-Newtonian fluids must be represented in terms
of boundary conditions, including the inlet flow velocity, the outlet pressure, and
the viscosity of the given fluid. These boundary conditions describe the given fluid’s
interaction with the scaffold’s surface [139,140].
(ii) Solver: This module focuses on applying numerical methods within CFD to solve
the governing equations, such as the Navier–Stokes (NS) equations [141] for con-
tinuous flow modelling or the Lattice Boltzmann Method (LBM) for discrete flow
modelling [142]. Traditionally, finite difference methods (FDM) using grids for the
discretisation of a given geometry were applied to solve the governing equations,
but they were inefficient for complex geometries [143]. The methods of FEM and
the finite volume method (FVM) have since gained popularity in CFD simulations
for complex and curved geometries. In FEM, geometry is divided into more minor
finite elements, primarily using mesh nodes. At the same time, FVM discretises the
problem into small control volumes centred around mesh points, focusing on the
conservation of physical quantities across each volume [144]. FEM is highly versatile
and is particularly effective for problems involving complex geometries and irregular
shapes. However, it becomes very computationally expensive for models with a large
number of elements. Comparatively, FVM is often considered more efficient for prob-
lems involving fluid dynamics and heat transfer, mainly because it directly applies
the conservation laws of mass, momentum, and energy over control volumes [145].
This type makes it naturally suited for the analysis of flow problems and can lead to
more accurate results in these cases with less computational effort.
(iii) Post Processing: After the CFD simulation, a post-processing module is used to anal-
yse the results, including the velocity streamlines, the average WSS, and pressure and
velocity contours. This analysis provides insights into how a scaffold’s architecture
affects fluid flow, offering valuable information about permeability, fluid velocity, and
WSS [146,147].
In fluid dynamics, a laminar flow occurs when the fluid flows smoothly without any
disturbance or deviation from its path. This type of flow typically happens at low velocities
or with high-viscosity fluids. Usually, the laminar occurs when a Reynolds number is lower
than a critical value of 2300. In contrast, fluid flows with a Reynolds number larger than
4000 are considered turbulent flow and generally involve swirling motions (eddies) and
deviations from the standard flow pattern. Fluid flow with a Reynolds number between
2300 and 3000 is considered transitional, indicating a shift from laminar to turbulent flow
characteristics [148,149].
Wang et al. [150] conducted a study using water as an incompressible fluid with
an inlet velocity of 1 mm/s and a zero-outlet pressure in their laminar CFD model to
predict permeability and the WSS of honeycomb structures in the context of cancellous
bone repair applications. This study concluded that the permeability of scaffolds between
15 and 48 µm2 has a positive influence on cancellous bone tissue regeneration. At the same
time, a WSS value between 2.8 and 42.8 mPa can simulate cell growth inside scaffolds
(Figure 15) [150].
Using blood as the fluid material in simulations, rather than water, offers more realistic
predictions of permeability and WSS within scaffolds. This simulation type is particularly
relevant as turbulence flow is a crucial characteristic of blood circulation [151]. Omar
et al. [130] utilised a k-ω SST turbulence CFD model to predict flow velocities, pressure
drops and WSS in anatomically shaped bone scaffolds. In their model, they varied inlet
blood flow velocities from 1 to 9 mm/s and employed a convergence criterion of 10−4
for residual monitoring. Their findings indicated that for blood velocities ranging from
Computation 2024, 12, 74 17 of 29

1 to 5 mm/s, the predicted WSS value was lower than 30 mPa. In contrast, for velocities
exceeding 5 mm/s, the predicted WSS value was higher than 30 mPa. The study also
observed that the value of WSS was generally lower in the centre of scaffolds and increased
near the wall of scaffolds (Figure 16) [130].
Blood is composed of plasma, ‘thrombocytes (platelets), leukocytes (white blood cells),
and erythrocytes (red blood cells)’ [152]. As previously mentioned, blood exhibits non-
Newtonian flow characteristics due to well-deformed high clusters of erythrocytes [153].
Various non-Newtonian blood viscosity models have been employed, such as the power
Computation 2024, 12, 74 law, generalised power law, Casson, Carreau, and Carreau–Yasuda models to model 17 ofblood
31

flow and WSS distributions in blood vessels [154,155].

Figure 13. Steps in formulating a mathematical model in a CFD simulation [137].

Figure 13. Steps in formulating a mathematical model in a CFD simulation [137].

Seehanam et al. [156] applied the Carreau–Yasuda viscosity model on sheet-based

gyroid scaffolds to predict pressure drops, velocity profiles and fluid-induced WSS in
comparison with a Newtonian flow model. This model was performed to study the influ-
ence of shear rate on blood viscosity. The findings revealed that the predicted parameters
from the non-Newtonian model were twice those predicted using the Newtonian model.
Additionally, both models predicted shear stress in the range between 0.05 and 10 mPa,
which is considered beneficial for the promotion of bone cell proliferation (Figure 17) [156].
A significant challenge in CFD simulation is generating clean meshes for complex
geometry structures such as TPMS structures and Voronoi lattices when computational
power is limited [157]. To overcome this limitation, Reduan et al. developed a new
Computation 2024, 12, 74 18 of 29

analytical model based on Hagen–Poiseuille’s law for permeability prediction of TPMS-

based bone scaffolds, which relies on morphological parameters. This model utilises
pressure drop values derived from CFD analysis to calibrate and refine the analytical
model, thus offering an effective workaround for computational limitations in the analysis
ofFigure 13. Steps
complex in formulating
scaffolds (Figure a18)
mathematical
[158]. model in a CFD simulation [137].

Figure14.
Figure 14. An
An illustration
illustration (designed
(designedusing
usingnTopology
nTopologysoftware version
software version4.22.2) of creating
4.22.2) a fluid
of creating a fluid
domain for CFD by using Boolean subtraction of solid (bioreactor) by scaffold lattice; the top region
Computation 2024, 12, 74 domain for CFD by using Boolean subtraction of solid (bioreactor) by scaffold lattice; the top18 region
of the fluid domain can be used as a velocity inlet of flow, and its bottom region can be used as aof 31
ofpressure
the fluid domain
outlet.
can be used as a velocity inlet of flow, and its bottom region can be used as a
pressure outlet.

Figure 15. (A) Pressure drops and (B) WSS contours of hexagonal honeycomb scaffolds based on (a)
Figure
Simple 15. (A) Pressure
Uniform drops
structure, and (B) WSSSimple
(b) Overlapping contours of hexagonal
Curved structure,honeycomb scaffolds structure,
(c) Simple Gradient based on
(a) Simple Uniform structure, (b) Overlapping Simple Curved structure, (c) Simple Gradient structure,
and (d) Simple Internal Curved structure. Reproduced with permission from Ref. [150] CC BT-NC- and
(d) Simple
ND 4.0. Internal Curved structure. Reproduced with permission from Ref. [150] CC BT-NC-ND 4.0.

Using blood as the fluid material in simulations, rather than water, offers more real-
istic predictions of permeability and WSS within scaffolds. This simulation type is partic-
ularly relevant as turbulence flow is a crucial characteristic of blood circulation [151].
Omar et al. [130] utilised a k-ω SST turbulence CFD model to predict flow velocities, pres-
Computation 2024,12,
Computation2024, 12,7474 19 of
of 29
31

Figure
Figure 16. (A) Pressure
16. (A) Pressuredrops,
drops,(B)(B)WSS
WSSand and(C)(C) velocity
velocity contours
contours of anatomically
of anatomically shaped
shaped BTE BTE
scaf-
scaffolds
folds forfor inlet
inlet blood
blood velocities:
velocities: (a)(a) 1 mm/s,
1 mm/s, (b)(b) 3 mm/s,
3 mm/s, (c) (c) 5 mm/s,
5 mm/s, (d) (d) 7 mm/s
7 mm/s andand
(e) (e) 9 mm/s.
9 mm/s. Re-
Reproduced
produced with withpermission
permissionfrom
fromRef.
Ref.[130]
[130]CC
CCBY BY4.0.
4.0.
 Seehanam et al. [156] applied the Carreau–Yasuda viscosity model on sheet-based
gyroid scaffolds to predict pressure drops, velocity profiles and fluid-induced WSS in
comparison with a Newtonian flow model. This model was performed to study the influ-
ence of shear rate on blood viscosity. The findings revealed that the predicted parameters
from the non-Newtonian model were twice those predicted using the Newtonian model.
Computation 2024, 12, 74
Additionally, both models predicted shear stress in the range between 0.05 and 10 20 of 29
mPa,
which is considered beneficial for the promotion of bone cell proliferation (Figure 17) [156].

Computation 2024, 12, 74 21 of 31

Figure 17. (a,b) Velocity contours and (c,d) WSS contours of Newtonian and non-Newtonian CFD
Figure 17.of(a,b)
models Velocity contours and (c,d) WSS contours of Newtonian and non-Newtonian CFD
offering angyroid scaffolds
effective with relative
workaround density 0.1. Reproduced
for computational with
limitations in permission from
the analysis Ref. [156]
of complex
models of gyroid 4.0.
CC BY-NC-ND scaffolds with relative density 0.1. Reproduced with permission from Ref. [156] CC
scaffolds (Figure 18) [158].
BY-NC-ND 4.0.
A significant challenge in CFD simulation is generating clean meshes for complex
geometry structures such as TPMS structures and Voronoi lattices when computational
power is limited [157]. To overcome this limitation, Reduan et al. developed a new ana-
lytical model based on Hagen–Poiseuille’s law for permeability prediction of TPMS-based
bone scaffolds, which relies on morphological parameters. This model utilises pressure
drop values derived from CFD analysis to calibrate and refine the analytical model, thus

Figure 18. CFD for permeability prediction of TPMS scaffolds to optimise innovative BTE implants.
Figure 18. CFD for permeability prediction of TPMS scaffolds to optimise innovative BTE implants.
Reproduced with permission from Ref. [158] CC BY-NC-ND 4.0.
Reproduced with permission from Ref. [158] CC BY-NC-ND 4.0.
Table 3. CFD modelling of fluid behaviour.

Predicted Fluid
Model and Other Proper- Fluid Material * Remarks
ties
Evaluation of the influence of morphologi-
Blood
cal parameters of uniform and graded
Computation 2024, 12, 74 21 of 29

Table 3. CFD modelling of fluid behaviour.

Predicted Fluid and

Model Fluid Material * Remarks
Other Properties
Evaluation of the influence of
Blood morphological parameters of uniform
Permeability and (Density: 1050 kg/m3 , and graded Schwartz-Primitive
WSS viscosity: 0.004 kg/(m.s), inlet scaffolds on their permeability
Steady-state Laminar velocity: 0.3 mL/min) properties for trabecular bone
fluid flow model applications [159]
Blood
Pressure drops, Evaluation of fluid transport properties
(Viscosity: 3.2 × 10−3 Pa.s,
permeability, and of Tra-PLA/PDA/COS@EU scaffolds
density: 1060 kg/m3 , inlet
WSS for trabecular bone repair [116]
velocity: 1 mm/s)
α-MEM Prediction of hydrodynamic responses
Laminar fluid flow model WSS, flow rate,
(Density: 1000 kg/m3 , for osteogenesis inside titanium
with Wang–Tarbell formula permeability, and
viscosity: 1.45 × 10−3 Pa.s, alloy-based TPMS and Voronoi
for permeability mass flow
inlet velocity: 1 mm/s) scaffolds [160]
Blood Prediction of fluid shear stress on
Incompressible Laminar Permeability, FSS, (Density: 1060 kg/cm3 , Voronoi scaffold surface, MSCs
Newtonian fluid model and and distribution of viscosity: 0.003 kg/m/s) attachment on the scaffold and
Discrete phase model (DPM) stem cells MSCs (Diameter: 12.7 µm, mechano-regulation osteoblast
and density: 1140 kg(m3 ) differentiation (MrOD) [161]
Prediction of WSS using support vector
Incompressible Newtonian Permeability, Body Fluid machines and eXtreme Gradient
fluid model and Machine pressure drop and (Density: 1056 kg/m3 , Boosting ML models to minimise the
Learning (ML) specific surface area viscosity: 0.0045 Pa.s) computational cost of CFD
simulations [162]
Blood
(Density: 1050 kg/m3 ,
Power law models for minimum and maximum Prediction of transport properties
Permeability and
incompressible dynamic viscosities: 0.001 and inside open cell Neovius TPMS
WSS
non-Newtonian fluid 0.708 kg/m/s, consistency scaffolds for BTE [163]
index: 0.017 kg.sn−2 /m,
power law exponent: 0.708)
Blood
(Density: 1050 kg/m3 , inlet
Pressure drops, velocity: 0.1 mm/s, lower and
Carreau–Yasuda
specific surface area, upper viscosities: 0.25 and Influence of pore size of TPMS scaffolds
non-Newtonian flow model
and cell seeding 0.0035 Pa.s) on cell seeding [164]
and DPM
efficiency MSCs (density: 1130 kg/m3 ,
diameter: 10 µm and initial
cell number: 3600)
Development of CFD models for
FEM-based CFD model with evaluation of perfusion bioreactor
Flow velocity and Culture medium
Brinkmann equation for shear systems to predict flow parameters of
shear stress (Inlet flow rate: 2 mL/min)
stress in scaffold medium β-Tricalcium phosphate scaffolds in
BTE [165]
Water
(Mass inflow: 1.5 g/min),
RANS K-Turbulence model Shear stress, flow Prediction of shear stress and nutrient
Glucose in tissues (Diffusion
and Transport of diluted distribution and distribution into tissues in a perfusion
coefficient: 6 × 10–10 m2 /s,
specimen model glucose diffusion bioreactor [166]
elimination rate: −1.157 +
10−4 mol/(m3 .s))
Computation 2024, 12, 74 22 of 29

Table 3. Cont.

Predicted Fluid and

Model Fluid Material * Remarks
Other Properties
DMEM
(Density: 1 g/cm3 , dynamic
viscosity: 1.45 mPa.s, inlet
Pressure drops, Flow Prediction of permeability of
velocity: 0.1, 1 to 10 mm/s,
SST K-ω Turbulence Model velocity distribution Magnesium-based trabecular bone
Thermal conductivity:
and WSS implants [167]
91 W/(mK), Specific Heat:
1050 J/(kg K), Electrical
resistivity: 6.20 × 10−8 Ω m)
Elastic energy (Cell
distribution),
Total/specific
Vertex hydrodynamics (VH) number of cells, Simulation of tissue growth at FGS in
Water
model intracellular perfusion bioreactors [168]
pressure, and
normalised shear
stress
MSCs (Stiffness: 50 to 150 µN,
Cell attachment rate Simulation of MSCs seeding on
bond strength: 0.025 to
LBM-based mesoscopic model and seeding uniform pore scaffold to evaluate cell
0.125 pN/nm, Binding force:
efficiency deformation and attachment [169]
10 to 50 pN)
α-MEM (Density: 993 kg/m3 ,
Two-relaxation time (TRT) Prediction of oxygen consumption to
viscosity: 10−3 Pa.s,
LBM with Fluid flow and the cells (MC3T3E1 Preosteoblasts) for
inlet velocity: 1.47 mm/s,
Michaelis–Menten-like kinetic oxygen transport optimal in vitro BTE methods of
oxygen diffusion coefficient:
model polysaccharide hydrogel scaffolds [170]
3 × 10−9 m2 /s)
* α-MEM: α-Modified Eagle’s Minimum cell culture medium with less vitamins, amino acids, and glucose; MEM:
Modified Eagle’s Minimum cell culture medium with more vitamins, amino acids, and glucose; DMEM: Dulbecco’s
Modified Eagle’s Medium; Tra-PLA/PDA/COS@EU: PLA with polydopamine and Chito Oligosaccharide-based
europium (III) organic ligands.

3. Conclusions
This review article has given an extensive analysis of the studies in FEM/CFD com-
putational modelling of scaffolds in BTE. It also gives introductory details about different
scaffold types based on parametric, non-parametric and stochastic designs to achieve sim-
ple to complex structures. The main challenge for computational engineers in BTE is to
select the appropriate material models for different mechanical loading in the case of FEM
modelling and to choose the suitable flow models for both Newtonian and non-Newtonian
fluids in the case of CFD modelling. Knowing the suitable models for the given problems
helps to accurately predict the equivalent mechanical properties and flow properties to
enhance scaffold designs, as well as to improve the bioreactor environment. Thus, the
prediction of these properties using computational modelling may be helpful in reducing
the cost of in vivo and in vitro examinations.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/computation12040074/s1, Figure S1: non-parametric designs
of scaffolds; Figure S2: parametric designs of scaffolds—TPMS; Figure S3: parametric designs of
scaffolds—Voronoi; Table S1: software tools to design TPMS/lattice-based scaffolds; Table S2: list of
FEM software; Table S3: list of CFD software.
Author Contributions: Conceptualisation, methodology, software, formal analysis, investigation,
resources, data curation, writing—original draft preparation, visualisation, H.-S.N.M.; writing—
review and editing, J.W. and M.D. All authors have read and agreed to the published version of
the manuscript.
Computation 2024, 12, 74 23 of 29

Funding: This research received no external funding.

Data Availability Statement: No data is associated for this review article.
Acknowledgments: (1.) I acknowledge Oraib Al-Ketan (New York University, Abu-Dhabi, UAE)
for providing his honest feedback for this manuscript and for providing ‘MSLattice PRO’ software
to design the TPMS gyroid scaffolds given in Supplementary Materials Figure S2g,h. (2.) I ac-
knowledge my academic supervisors, Dhayalan Velauthapillai/Talal Rahman (Western Norway
University of Applied Sciences, Bergen, Norway) and Kamal Mustafa (University of Bergen, Bergen,
Norway) for their academic support. (3.) I acknowledge nTopology Inc. (New York, USA) for
providing a non-commercial license of nTop software to design the scaffolds given in Figure 13,
Supplementary Materials Figures S1, S2a–f and S3.
Conflicts of Interest: The authors declare no conflicts of interest.

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